PXR-mediated Regulation of Placental Drug Transporters Impact on Fetal Exposure to Lopinavir
Year: 2014
Type: dissertation
Abstract: Globally, there are close to 20 million women living with HIV. An increasing number of these women are of child bearing age. Current guidelines recommend treatment of all pregnant women with highly active antiretroviral agents to both maintain maternal health and to prevent the vertical transmission of the virus. Maintaining a balance between adequate levels of antiretroviral in the fetal system and preventing fetal toxicity are key to the success of this strategy. Despite increasing use, little is known about the transplacental accumulation of these agents. ABC drug transporters at the placental surface are believed to play an important role in the protective function of the placenta. This thesis explored the involvement of Pregnane X Receptor (PXR), an established regulator of drug transporters in the liver and intestine, in the regulation of placental drug transporters and the impact of PXR genotype and associated differences in placental transporter levels on fetal drug accumulation of lopinavir, a key antiretroviral used extensively in pregnant women. We examined the role of the nuclear receptor at the placental interface in PXR knockout and wildtype mice. Pegnenolone-16-á-carbonitrile (PCN) treatment failed to induce PXR and target genes in the placenta in contrast to the liver. Furthermore, an inverse relationship between placental PXR expression and the expression of Pgp, Mrp 1-3 and Bcrp was observed in the placental tissue. PXR heterozygotes were bred in order to generate pregnant dams with varying expression of placental transporters in individual fetal units within the same dam. This model was used to study the impact of fetal genotype and placental transporter expression on fetal exposure to lopinavir within the same dam. A two fold higher fetal accumulation of lopinavir was observed the PXR null placentas as compared to the wild types. An inverse relationship was observed between the placental expression of Mdr1a and fetal exposure to lopinavir (p
Source: TSpace (University of Toronto)
Author: Sarabjit Gahir
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2953195376